Long-lasting remission induced by rituximab in two cases of refractory autoimmune haemolytic anaemia due to cold agglutinins

Dear Sir,

cold-agglutinin-induced autoimmune haemolytic anaemia (AIHA) can be a therapeutic challenge¹, for which rituximab has been used with favourable results^2–4. We report on two patients with refractory AIHA due to cold antibodies who were successfully treated with anti-CD20 monoclonal antibody in our institution.

Case 1

A 54-year old man came to our attention with a 2-year history of symptomatic AIHA due to cold antibodies. The diagnosis had been made in another hospital where he had received full doses of corticosteroids for 3 months without any benefit, and thus required repeated transfusions. He reported a long history of type 2 diabetes mellitus recently complicated by chronic renal failure. The patient had no personal or family history of hereditary haemolytic anaemia or autoimmune diseases. A careful reevaluation was performed. On physical examination the man was pale and had slight enlargement of both the spleen and liver but no lymphadenopathy. The laboratory findings, besides being consistent with the known diabetes mellitus and chronic renal failure, revealed normochromic and normocytic anaemia (haemoglobin, Hb = 7.5 g/dL) with reticulocytosis, and a typical haemolytic pattern. Autoimmune diseases and the most common viral infections were ruled out. Chest X-rays and total body computed tomography scans appeared normal. The blood film showed gross agglutinants. A bone marrow aspirate and a trephine biopsy demonstrated normal representation of myeloid and megakaryocytic precursors and erythroid hyperplasia with a moderate polyclonal lymphoplasmacytoid reaction. Immunohaematological investigations revealed a strongly positive direct antiglobulin test (DAT) and anti-C3 antisera with presence of a cold IgM (1:256) active from 4°C to 20°C. In order to obtain a comprehensive understanding of the chronic renal failure, a renal biopsy was also performed: features related to diabetic nephropathy with glomerulosclerosis and tubulo-interstitial fibrosis, but no signs of immune-mediated glomerular damage and/or immunoglobulin deposition, were found. A diagnosis of primary refractory AIHA due to cold antibodies was made so that, as salvage therapy, the patient was offered rituximab. The patient was properly informed and gave his consent. He, therefore, received rituximab as a 4-hour intravenous infusion at the dose of 375 mg/m² once weekly for a total of four doses, without any adverse reactions or side effects. A progressive increase of Hb levels followed the decrease of the reticulocyte count after the fourth dose of rituximab. Three months after the last dose of rituximab, the DAT became negative. Currently, at the 12-months follow-up, the patient’s Hb level is within the normal range, serum markers of haemolysis are normal the DAT is negative.

Case 2

A 39-year old woman was diagnosed as having AIHA due to cold IgM antibodies 1 year before in another centre. She was unsuccessfully treated with a 3-month course of full doses of prednisone. She, therefore, received cyclophosphamide which was given intravenously at a weekly dose of 500 mg for 4 weeks. However, at the cessation of cyclophosphamide, her haemolysis worsened. The patient was referred to our centre and evaluated for a salvage treatment. She presented with malaise and fatigue and reported typical cold-related manifestations of the disease. Her past medical history and physical examination were unremarkable. As for case 1, a comprehensive work-up was performed. No clonal lymphoproliferative disorder was found. Coombs’ test was positive for antiglobulin and anti-C3 antisera. An IgM cold agglutinin (1:512) with a thermal amplitude ranging from 0°C to 22°C was detected. After obtaining the patient’s informed consent, treatment with rituximab was started according to the same infusion schedule described above. The treatment was well-tolerated. Following the first dose of rituximab the patient’s Hb concentration rose from 8.0 to 11.90 g/L within 1 week. By the end of treatment, haemolytic markers had normalised and the Hb level had risen to 12.9 g/L. Three months after completing treatment, the DAT became only slightly detectable. Presently, 9 months since completing rituximab, the patient has a normal Hb together with a reticulocyte count and haemolytic markers within the normal ranges of values; the DAT is weakly positive.

Cold-agglutinin-induced AIHA is difficult to treat even using corticosteroids, immunosuppressive drugs, alkylating cytostatics, interferon, corticosteroids and splenectomy¹. In our patients, the disease activity could not be controlled by corticosteroids or, in one of them, by cyclophosphamide. The cases reported here add to the relatively sparse data on the use of rituximab in idiopathic cold AIHA. Initial results of treatment with this agent have been promising^2–4, with a response rate of approximately 60% and a reportedly favourable cost-effective profile through reducing transfusion needs⁵. Moreover, as it has been previously reported, rituximab was administered safely to the patient with chronic renal failure. In conclusion, in our experience, rituximab provided the means to obtain sustained remissions without the toxicities associated with corticosteroids and other immunosuppressive agents.